Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 233
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Nutr ; 154(3): 801-803, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38244860

RESUMEN

A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Obesidad , Tejido Adiposo , Orlistat , Pérdida de Peso , Peso Corporal
2.
Am J Physiol Gastrointest Liver Physiol ; 325(2): G147-G157, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37129245

RESUMEN

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.NEW & NOTEWORTHY We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fructosa/metabolismo , Dieta Alta en Grasa/métodos , Hígado/metabolismo , Colesterol/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
3.
Int J Mol Sci ; 24(4)2023 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-36835642

RESUMEN

Dietary lipids induce apolipoprotein A4 (APOA4) production and brown adipose tissue (BAT) thermogenesis. Administration of exogenous APOA4 elevates BAT thermogenesis in chow-fed mice, but not high-fat diet (HFD)-fed mice. Chronic feeding of HFD attenuates plasma APOA4 production and BAT thermogenesis in wildtype (WT) mice. In light of these observations, we sought to determine whether steady production of APOA4 could keep BAT thermogenesis elevated, even in the presence of HFD consumption, with an aim toward eventual reduction of body weight, fat mass and plasma lipid levels. Transgenic mice with overexpression of mouse APOA4 in the small intestine (APOA4-Tg mice) produce greater plasma APOA4 than their WT controls, even when fed an atherogenic diet. Thus, we used these mice to investigate the correlation of levels of APOA4 and BAT thermogenesis during HFD consumption. The hypothesis of this study was that overexpression of mouse APOA4 in the small intestine and increased plasma APOA4 production would increase BAT thermogenesis and consequently reduce fat mass and plasma lipids of HFD-fed obese mice. To test this hypothesis, BAT thermogenic proteins, body weight, fat mass, caloric intake, and plasma lipids in male APOA4-Tg mice and WT mice fed either a chow diet or a HFD were measured. When fed a chow diet, APOA4 levels were elevated, plasma triglyceride (TG) levels were reduced, and BAT levels of UCP1 trended upward, while body weight, fat mass, caloric intake, and plasma lipids were comparable between APOA4-Tg and WT mice. After a four-week feeding of HFD, APOA4-Tg mice maintained elevated plasma APOA4 and reduced plasma TG, but UCP1 levels in BAT were significantly elevated in comparison to WT controls; body weight, fat mass and caloric intake were still comparable. After 10-week consumption of HFD, however, while APOA4-Tg mice still exhibited increased plasma APOA4, UCP1 levels and reduced TG levels, a reduction in body weight, fat mass and levels of plasma lipids and leptin were finally observed in comparison to their WT controls and independent of caloric intake. Additionally, APOA4-Tg mice exhibited increased energy expenditure at several time points when measured during the 10-week HFD feeding. Thus, overexpression of APOA4 in the small intestine and maintenance of elevated levels of plasma APOA4 appear to correlate with elevation of UCP1-dependent BAT thermogenesis and subsequent protection against HFD-induced obesity in mice.


Asunto(s)
Tejido Adiposo Pardo , Obesidad , Ratones , Masculino , Animales , Tejido Adiposo Pardo/metabolismo , Ratones Transgénicos , Obesidad/metabolismo , Grasas de la Dieta/metabolismo , Dieta Alta en Grasa , Metabolismo Energético , Termogénesis , Ratones Endogámicos C57BL , Proteína Desacopladora 1/metabolismo
4.
J Nutr ; 152(11): 2387-2395, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36774105

RESUMEN

BACKGROUND: In vivo data on intestinal fat absorption in weanling piglets are scarce. OBJECTIVES: This study aimed to investigate the effect of weaning stress on intestinal fat absorption. METHODS: Eighteen 7-d-old sow-reared piglets (Duroc-Landrace-Yorkshire) were assigned to 3 groups (n = 6/group, 3 males and 3 females per group). Piglets were nursed by sows until 24 d of age (suckling piglets, S), or weaned at 21 d of age to a corn-soybean meal-based diet until 24 d (3 d postweaning, W3) or 28 d (7 d postweaning, W7) of age, respectively. Duodenum, jejunum, and ileum were collected to determine intestinal morphology and abundance of proteins related to fat absorption. RESULTS: Compared with the S group, the W3 group had lower villus height (17-34%) and villus height to crypt depth ratio (13-53%), as well as 1-1.45 times greater crypt depth; these values were 1.18-1.31, 0.69-1.15, and 1.47-1.87 times greater in the W7 group than in the W3 group, respectively. Compared with the S group, weaning stress for both W3 and W7 groups reduced intestinal alkaline phosphatase activity (26-73%), serum lipids (26-54%), and abundances of proteins related to fatty acid transport [fatty acid transport protein 4 (FATP4) and intestinal fatty acid-binding protein (I-FABP)] and chylomicron assembly [microsomal triglyceride transfer protein (MTTP), apolipoprotein A-IV (APOA4), B (APOB), and A-I (APOA1)] in the duodenum and ileum (10-55%), as well as in the jejunum (25-85%). All these indexes did not differ between W3 and W7 groups. Compared with the S group, the W3 group had lower mRNA abundances of duodenal APOA4 and APOA1 (25-50%), as well as jejunal FATP4, IFABP, MTTP, APOA4, and APOA1 (35-50%); these values were 5-15% and 10-37% lower in the W7 group than in the W3 group, respectively. CONCLUSIONS: Weaning stress in piglets attenuates the expression of intestinal proteins related to fatty acid transport (FATP4 and I-FABP) and chylomicron synthesis (APOA4).


Asunto(s)
Intestinos , Yeyuno , Masculino , Porcinos , Animales , Femenino , Destete , Mucosa Intestinal/metabolismo , Absorción Intestinal , Ácidos Grasos/metabolismo , Suplementos Dietéticos
5.
Circ Res ; 127(10): 1236-1252, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-32820707

RESUMEN

RATIONALE: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. OBJECTIVE: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. METHODS AND RESULTS: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient (Apoe-/-) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. CONCLUSIONS: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.


Asunto(s)
Apolipoproteína A-I/metabolismo , Microbioma Gastrointestinal , Hígado/metabolismo , Receptor Toll-Like 5/metabolismo , Animales , Apolipoproteína A-I/genética , HDL-Colesterol/metabolismo , Grasas de la Dieta/metabolismo , Flagelina/metabolismo , Flagelina/farmacología , Ratones , FN-kappa B/metabolismo , Receptor Toll-Like 5/efectos de los fármacos
6.
J Physiol ; 599(22): 5015-5030, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34648185

RESUMEN

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether oestradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [3 H]-TAG lymphatic output through reducing TAG transport; and P treatment decreased [14 C]cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signalling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. KEY POINTS: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Oestrogen treatment significantly reduced [3 H]triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [14 C]cholesterol in lymph by inhibiting cholesterol absorption in the OVX rats. Oestrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.


Asunto(s)
Caracteres Sexuales , Factor A de Crecimiento Endotelial Vascular , Animales , Grasas de la Dieta/metabolismo , Femenino , Absorción Intestinal , Mucosa Intestinal/metabolismo , Linfa , Sistema Linfático , Masculino , Ratones , Ratas , Triglicéridos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
J Surg Res ; 260: 399-408, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33261855

RESUMEN

BACKGROUND: We have optimized a technique for cannulation of mesenteric lymph duct (MLD) in mice. Mice have low rates of intestinal lymph production; the MLDs are smaller and associated with fragile vasculature. Previous protocols for lymph collection based on the open lymph fistula model were associated with low success rates in mice. Bariatric surgery procedures worsen success rates due to postoperative adhesions and GI rearrangement. We have used this procedure to collect mesenteric lymph from mice undergoing bile diversion from gall bladder to ileum (GB-IL). HYPOTHESIS: We hypothesize that peptide YY (PYY) levels in mesenteric lymph will increase following nutrient delivery in mice undergoing bile diversion from gall bladder to ileum (GB-IL). METHODS AND RESULTS: We observe that cannulation of the MLD using a needled-catheter maintains lymph vessel integrity, prevents excessive lymph leakage, and is less traumatic, leading to high success rates (>95%). PYY levels in mesenteric lymph after GB-IL were significantly higher post nutrient infusion. The procedure takes approximately 20 min; small rodent surgical experience and practice are required for success. CONCLUSIONS: Intestinal lymph can be collected from mice, including those undergoing bariatric surgical procedures with high success rates by cannulation of the mesenteric lymph duct.


Asunto(s)
Cirugía Bariátrica , Procedimientos Quirúrgicos del Sistema Biliar , Cateterismo/métodos , Linfa/metabolismo , Vasos Linfáticos/cirugía , Mesenterio/cirugía , Péptido YY/metabolismo , Animales , Bilis , Biomarcadores/metabolismo , Femenino , Vesícula Biliar/cirugía , Íleon/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales
8.
J Lipid Res ; 61(2): 244-251, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31831525

RESUMEN

APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid.


Asunto(s)
Apolipoproteína A-V/metabolismo , Animales , Apolipoproteína A-V/biosíntesis , Apolipoproteína A-V/aislamiento & purificación , Escherichia coli/citología , Escherichia coli/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Recombinantes/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G23-G35, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32421358

RESUMEN

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells (EECs) in response to nutrient ingestion and lower blood glucose levels by stimulation of insulin secretion and thus are defined as incretins. GLP-1 receptor (GLP-1R) expression has been identified on enteric neurons that include intrinsic afferent neurons, extrinsic spinal, and vagal sensory afferents but has not been shown to have an incretin effect through these nerves. GLP-1 and GIP enter the mesenteric lymphatic fluid (MLF) after a meal via the interstitial fluid (IF) from local tissue secretion and/or blood capillaries. We tested if MLF could induce diet-dependent intransient increases in intracellular calcium ([Ca2+]i) in cultured sensory neurons. Postprandial rat MLF, collected from the superior mesenteric lymphatic duct, induced a significant twofold higher intransient increase in [Ca2+]i in primary-cultured sensory neurons than MLF from fasted rats. Inhibition of transient receptor potential vanilloid 1 (TRPV1) and TRPV1 and ankyrin 1 cation channels (TRPA1) with ruthenium red eliminated the difference. Substance P (SP) (a peptide that stimulates insulin secretion) sensor cells cocultured with sensory neurons showed both the GLP-1R agonist exendin-4 (Ex-4) and GIP induced transient increases in [Ca2+]i directly coupled to SP secretion in the sensory nerves. Ex-4-induced release of SP required expression of either TRPA1 or TRPV1. These data identify unrecognized actions of GLP-1 and GIP as incretins by acting as neurolymphocrines and suggest a mechanism for sensory nerves to respond to the postprandial state through MLF.NEW & NOTEWORTHY Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted upon eating to lower blood sugar. GLP-1 and GIP were found to induce the secretion of substance P (SP) from cultured sensory nerves. SP enhances insulin secretion. Mesenteric lymphatic fluid (MLF) also stimulates sensory neurons in a diet-dependent manner. These studies identify new actions of GLP-1 and GIP as incretins and suggest a mechanism for sensory nerves to respond to diet through MLF.


Asunto(s)
Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Sustancia P/metabolismo , Canal Catiónico TRPA1/metabolismo , Animales , Glucemia/metabolismo , Células Enteroendocrinas/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Incretinas/metabolismo , Periodo Posprandial , Ratas , Receptores de la Hormona Gastrointestinal
10.
Arterioscler Thromb Vasc Biol ; 39(8): 1565-1573, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31294621

RESUMEN

OBJECTIVE: Dietary triglycerides are partially retained in the intestine within intracellular or extracellular compartments, which can be rapidly mobilized in response to several stimuli, including glucose and GLP-2 (glucagon-like peptide-2). To elucidate the mechanism of intestinal lipid mobilization, this study examined the patterns and time course of lymph flow and triglycerides after glucose and GLP-2 treatment in rats. Approach and Results: Lymph flow, triglyceride concentration, and triglyceride output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal (i.d.) lipid bolus followed 5 hours later by either (1) i.d. saline+intraperitoneal (i.p.) saline (placebo), (2) i.d. glucose plus i.p. saline, (3) i.d. saline+i.p. GLP-2, or (4) i.d. glucose+i.p. GLP-2. GLP-2 and glucose administered alone or in combination stimulated total triglyceride output to a similar extent, but the timing and pattern of stimulation differed markedly. Whereas GLP-2 rapidly increased lymph flow with no effect on lymph triglyceride concentration or triglyceride:apoB48 (apolipoprotein B48) ratio (a surrogate marker of chylomicron size) compared with placebo, glucose transiently decreased lymph flow followed by delayed stimulation of lymph flow and increased lymph triglyceride concentration and triglyceride:apoB48 ratio. CONCLUSIONS: Glucose and GLP-2 robustly enhanced intestinal triglyceride output in rats but with different effects on lymph flow, lymph triglyceride concentration, and chylomicron size. GLP-2 stimulated triglyceride output primarily by enhancing lymph flow with no effect on chylomicron size, whereas glucose mobilized intestinal triglycerides, stimulating secretion of larger chylomicrons. This suggests that these 2 stimuli mobilize intestinal lipid by different mechanisms.


Asunto(s)
Péptido 2 Similar al Glucagón/farmacología , Glucosa/farmacología , Mucosa Intestinal/metabolismo , Triglicéridos/metabolismo , Animales , Apolipoproteína B-48/análisis , Quilomicrones/metabolismo , Linfa/efectos de los fármacos , Linfa/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley
11.
J Biol Chem ; 293(34): 13349-13350, 2018 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-30143599

RESUMEN

Mice harboring a particular allele of the human brain-derived neurotropic factor (BDNFM/M mice) develop extreme obesity and insulin resistance when fed a high-fat diet. The underlying mechanisms of this genetic risk factor for obesity are unclear. In the current issue of JBC, Yang et al. report that pharmacological inhibition of integral membrane protein CD36 significantly reduces body weight gain and improves glucose tolerance in BDNFM/M mice. Targeting CD36 may therefore be a promising strategy to improve metabolic dysfunctions and normalize risk factors in obese individuals.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Antígenos CD36/metabolismo , Enfermedades Metabólicas/fisiopatología , Mutación , Obesidad/fisiopatología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Humanos , Ratones
12.
J Biol Chem ; 293(6): 2091-2101, 2018 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-29263093

RESUMEN

We previously found that 17ß-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.


Asunto(s)
Apolipoproteínas A/genética , Estradiol/metabolismo , Estrógenos/metabolismo , Coactivador 1 de Receptor Nuclear/genética , Obesidad/genética , Núcleo Solitario/metabolismo , Animales , Apolipoproteínas A/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Alimentos , Femenino , Silenciador del Gen , Humanos , Coactivador 1 de Receptor Nuclear/metabolismo , Obesidad/metabolismo , Obesidad/fisiopatología , Ovariectomía , Ratas , Ratas Long-Evans
13.
Gastroenterology ; 155(2): 501-513, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29689264

RESUMEN

BACKGROUND & AIMS: Intestinal microbiota modulate metabolism and associate closely with epithelial cells in the intestine. In intestinal epithelial cells (IECs), histone deacetylase 3 (HDAC3) integrates microbiota-derived signals to control intestinal homeostasis. We investigated whether HDAC3 in IECs regulates metabolism and the development of obesity in mice. METHODS: Adult C57BL/6 (control) mice and mice with constitutive or inducible IEC-specific disruption of Hdac3 (HDAC3ΔIEC mice) were placed on a standard chow or high-fat diet (HFD, 60% kcal from fat). We measured body composition, weight, glucose tolerance, and energy expenditure. IECs were isolated from small intestine and gene expression, and lipid levels were analyzed. HDAC3 levels were determined in 43 pediatric patient ileal biopsy samples and compared with body weight. RESULTS: Control mice fed an HFD gained weight, became obese, and had reduced glucose tolerance with increased serum insulin, whereas HFD-fed HDAC3ΔIEC mice did not develop obesity. Serum levels of triglycerides were reduced in HDAC3ΔIEC mice, and these mice had less liver fat and smaller adipocytes, compared with HFD-fed control mice. HDAC3ΔIEC mice had similar food intake and activity as control mice, but higher energy expenditure because of increased catabolism. IECs from HDAC3ΔIEC mice had altered expression levels of genes that regulate metabolism in response to the microbiota (such as Chka, Mttp, Apoa1, and Pck1) and accumulated triglycerides compared with IECs from control mice. The microbiota-derived short-chain fatty acid butyrate was decreased in obese mice. Butyrate significantly reduced the activity of HDAC3 and increased Pck1 expression in only control IECs. Administration of butyrate to control mice with diet-induced obesity, but not HDAC3ΔIEC mice, led to significant weight loss. Disruption of HDAC3 in IECs of mice after they became obese led to weight loss and improved metabolic profile. Levels of HDAC3 in intestinal biopsy samples correlated with patient weight. CONCLUSIONS: We found that epithelial HDAC3 promotes development of diet-induced obesity in studies of mice and that butyrate reduces activity of HDAC3 in IECs to prevent diet-induced obesity. This pathway might be manipulated to prevent or reduce obesity-associated disease.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Células Epiteliales/metabolismo , Microbioma Gastrointestinal/fisiología , Histona Desacetilasas/metabolismo , Obesidad/patología , Animales , Biopsia , Peso Corporal/fisiología , Niño , Modelos Animales de Enfermedad , Metabolismo Energético , Femenino , Histona Desacetilasas/genética , Humanos , Íleon/citología , Íleon/microbiología , Íleon/patología , Resistencia a la Insulina , Mucosa Intestinal/citología , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad/etiología , Obesidad/fisiopatología
14.
Biol Reprod ; 100(4): 1073-1081, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30418498

RESUMEN

L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1α (Atp1a1), fatty acid transporter Slc27a4, and glucose transporters Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis.


Asunto(s)
Suplementos Dietéticos , Viabilidad Fetal/efectos de los fármacos , Fenómenos Fisiologicos Nutricionales Maternos , Nutrientes/farmacocinética , Placenta/metabolismo , Placentación/efectos de los fármacos , Prolina/farmacología , Sistemas de Transporte de Aminoácidos/metabolismo , Líquido Amniótico/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Embrión de Mamíferos , Femenino , Desarrollo Fetal/efectos de los fármacos , Fenómenos Fisiologicos Nutricionales Maternos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Placenta/efectos de los fármacos , Embarazo
15.
Am J Physiol Gastrointest Liver Physiol ; 315(1): G95-G103, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29470144

RESUMEN

Breast milk lutein is better absorbed by infants than lutein delivered in infant formula. Therefore, we wanted to better understand the possible absorption differences of lutein in breast milk vs. that in infant formula by determining its bioavailability after gastric administration and whether the intestinal absorption of lutein can be improved by using new delivery vehicles. Study 1 compared the intestinal uptake,and the lymphatic and portal transport of lutein in conscious lymph fistula rats. Four groups of lymph- and portal vein-cannulated rats ( n = 8-10/group) were randomized to receive via gastric tube increasing doses (10, 20, 40, or 80 mg/kg) of 20% lutein in safflower oil (SO) suspension to assess whether there was a saturable level of lutein that could be absorbed and transported in lymph. Aliquots of hourly portal blood and lymph were taken for lutein and zeaxanthin analyses. The dose-response study showed that 20 mg/kg lutein was the saturable level of lymphatic lutein absorption with no lutein detected in portal circulation at any dosage level tested. Study 2 randomized five groups of lymph fistula rats ( n = 4-9/group) to receive 20 mg/kg lutein from either lutein in SO or lutein in four different mono- and diglyceride oils (MDGs). Gastric infusion of lutein suspended in MDG (20 mg/kg) significantly improved (71-211%, P < 0.05) lymphatic lutein output 2-6 h after lipid feeding vs. lutein in SO. Lymphatic zeaxanthin (10% of the lutein fed mixture) transport in both Study 1 and Study 2 followed that of lutein. We conclude that a mixture of MDGs helps solubilize lutein and facilitate gastrointestinal micelle formation, thus improving lymphatic lutein absorption compared with triglyceride oils. NEW & NOTEWORTHY This paper describes how lutein is digested and absorbed by the gastrointestinal tract by using the conscious lymph fistula rat model. Our dose-response study showed that absorption and lymphatic transport of lutein is a saturable process with no lutein detected in portal circulation at any dosage level tested. Our paper also provides insight into how this process can be improved by modifying the typical lipid mixtures carrying the lutein.


Asunto(s)
Transporte Biológico/fisiología , Diglicéridos , Absorción Intestinal , Luteína , Monoglicéridos , Animales , Disponibilidad Biológica , Factores Biológicos/metabolismo , Factores Biológicos/farmacología , Diglicéridos/metabolismo , Diglicéridos/farmacología , Relación Dosis-Respuesta a Droga , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Mucosa Intestinal/metabolismo , Luteína/metabolismo , Luteína/farmacología , Sistema Linfático/fisiología , Modelos Animales , Monoglicéridos/metabolismo , Monoglicéridos/farmacología , Sistema Porta/fisiología , Ratas
16.
Curr Opin Gastroenterol ; 34(2): 59-70, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29266008

RESUMEN

PURPOSE OF REVIEW: The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. RECENT FINDINGS: The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. SUMMARY: The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G/genética , Colelitiasis/genética , Modelos Animales de Enfermedad , Cálculos Biliares/genética , Animales , Colelitiasis/fisiopatología , Cálculos Biliares/fisiopatología , Predisposición Genética a la Enfermedad/genética , Humanos , Ratones
17.
Gastroenterology ; 151(5): 923-932, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27436071

RESUMEN

BACKGROUND & AIMS: The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process. METHODS: Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters. RESULTS: Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended. CONCLUSIONS: The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons.


Asunto(s)
Antibacterianos/farmacología , Grasas de la Dieta/metabolismo , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mastocitos/efectos de los fármacos , Penicilinas/farmacología , Estreptomicina/farmacología , Animales , Antibacterianos/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Absorción Intestinal/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Mastocitos/metabolismo , Mastocitos/microbiología , Penicilinas/administración & dosificación , Permeabilidad , Ratas , Ratas Sprague-Dawley , Estreptomicina/administración & dosificación
18.
Biochem Biophys Res Commun ; 487(2): 327-332, 2017 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-28412351

RESUMEN

ApoA4 exerts anti-inflammatory effects, but the mechanism remains unclear. SERPINA3 is a member of the serine proteinase inhibitor gene family, and has been shown to be involved in anti-inflammation and associated with a number of human diseases. In this study, we revealed that ApoA4 stimulates the gene expression of SERPINA3 in mouse hepatocytes both in vivo and in vitro, in a dose- and time-dependent manner. The transcriptional response of SERPINA3 to ApoA4 is regulated through the binding of ApoA4 with nuclear receptors NR4A1 and NR1D1 on the SERPINA3 promoter, which was verified with ChIP, Luciferase activity assay and RNA interference-mediated NR4A1 or NR1D1 gene knockdown. These data suggests that ApoA4 transcriptionally induced SERPINA3 expression via NR1D1 and NR4A1. Our findings may throw light on the function of ApoA4 in inflammatory responses and acute-phase reactions, as well as the development of SERPINA3 relative diseases.


Asunto(s)
Apolipoproteínas A/farmacología , Hepatocitos/metabolismo , Hígado/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Serpinas/metabolismo , Animales , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos/fisiología , Distribución Tisular
19.
Am J Physiol Regul Integr Comp Physiol ; 313(5): R535-R548, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28768657

RESUMEN

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.


Asunto(s)
Apolipoproteínas A/metabolismo , Colecistoquinina/metabolismo , Grasas de la Dieta/metabolismo , Homeostasis/fisiología , Adiposidad/genética , Adiposidad/fisiología , Animales , Apolipoproteínas A/deficiencia , Peso Corporal/fisiología , Colecistoquinina/deficiencia , Dieta con Restricción de Grasas/métodos , Ingestión de Alimentos/fisiología , Ingestión de Energía/fisiología , Metabolismo Energético/genética , Ratones Noqueados
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA